EP0107544A2 - Automatische Anlage für Flüssigkeitschromatograpie - Google Patents

Automatische Anlage für Flüssigkeitschromatograpie Download PDF

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Publication number
EP0107544A2
EP0107544A2 EP83401880A EP83401880A EP0107544A2 EP 0107544 A2 EP0107544 A2 EP 0107544A2 EP 83401880 A EP83401880 A EP 83401880A EP 83401880 A EP83401880 A EP 83401880A EP 0107544 A2 EP0107544 A2 EP 0107544A2
Authority
EP
European Patent Office
Prior art keywords
column
product
fractionated
container
eluent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP83401880A
Other languages
English (en)
French (fr)
Other versions
EP0107544A3 (en
EP0107544B1 (de
Inventor
Pierre Noel Girot
Egisto Boschetti
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmuka Laboratoires SA
Original Assignee
Pharmuka Laboratoires SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharmuka Laboratoires SA filed Critical Pharmuka Laboratoires SA
Publication of EP0107544A2 publication Critical patent/EP0107544A2/de
Publication of EP0107544A3 publication Critical patent/EP0107544A3/fr
Application granted granted Critical
Publication of EP0107544B1 publication Critical patent/EP0107544B1/de
Expired legal-status Critical Current

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
    • B01D15/08—Selective adsorption, e.g. chromatography
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
    • B01D15/08—Selective adsorption, e.g. chromatography
    • B01D15/10—Selective adsorption, e.g. chromatography characterised by constructional or operational features
    • B01D15/24—Selective adsorption, e.g. chromatography characterised by constructional or operational features relating to the treatment of the fractions to be distributed
    • B01D15/247—Fraction collectors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N30/16—Injection
    • G01N30/22—Injection in high pressure liquid systems
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N30/24—Automatic injection systems

Definitions

  • the subject of the present invention is an automatic installation for liquid chromatography, installation of the type comprising a chromatography column, a container for product to be fractionated and at least one container for eluent, these containers being able to be placed in communication with the top of the column by the intermediary of an injection pump, a detection device connected at the outlet of the column and providing at least one measurement signal representative of a characteristic of the liquid leaving the bottom of the column, a device for collecting fractions with at less a collecting container which can be placed in communication with the bottom of the column by means of an automatically controlled outlet valve, and a control unit receiving the measurement signal and comprising means for controlling the fraction collection device .
  • Chromatography is a process for separating the constituents of a mixture, a process which can be used for analytical or industrial purposes.
  • the field of application of the invention is more particularly, but not exclusively, that of industrial chromatography.
  • the collecting containers are arranged on a conveyor, for example a rotary plate, which is moved step by step.
  • the object of the present invention is to provide a fully automated liquid chromatography installation capable of carrying out successive chromatography cycles without the results being affected by variations in operating parameters such as the flow rate of liquid in the column.
  • the present invention also aims to provide a liquid chromatography installation requiring only very light monitoring by an operator without risk of degradation of the column or loss of product.
  • the various operations carried out during a cycle are not controlled at time intervals fixed in advance but are carried out at instants determined according to the information provided by the detection device.
  • the use of a metering device makes it possible to automatically carry out successive cycles without operator intervention other than those necessary to periodically fill the containers with product to be fractionated and eluent and empty the collecting container (s).
  • the safety device prevents accidental injection of air, which would put the column out of order.
  • the detection device includes several detectors for supplying different measurement signals representative of different characteristics of the liquid leaving the column.
  • the control device includes, so known per se, a comparator for triggering the collection of a fraction when a measurement signal supplied by the detection device crosses in a direction a first predetermined adjustable threshold.
  • the control device comprises a second comparator for interrupting the collection of the fraction when the measurement signal crosses in the other direction a second predetermined threshold adjustable independently of the first.
  • the eluent admission is for example ordered in response to the end of the injection of the product to be fractionated. or at the end of the collection of a fraction.
  • the collection of the different fractions is carried out in different collecting vessels.
  • the different collecting containers could be placed on a conveyor device bringing them successively in the sampling position, a single outlet valve being provided to put the column in communication with the different collecting containers.
  • the volumes treated are relatively large and it is then preferable to use several collecting vessels with a fixed station, in number at least equal to that of the fractions to be collected.
  • Each collecting container can be placed in communication with the column either by means of a common outlet valve with the interposition of a dispensing device, or by means of a particular outlet valve controlled by the control device.
  • a level detector is associated with each collecting container to provide a high level signal when the liquid level in the container becomes greater than a predetermined threshold, and is connected to the safety device to prevent collection of this liquid when the high level signal is present.
  • the process is stopped when a container of product to be fractionated or eluent risks emptying or that a collecting container risks overflowing.
  • the level signals can also be used to activate an alarm indicating to the operator that the filling or emptying of a container is necessary.
  • the installation shown in FIG. 1 comprises a container 10 for product to be fractionated, with which is associated a metering bottle 10 ', and several containers with eluent 11 to 16.
  • a solenoid valve V'10 is mounted on a line C10 connecting the container 10 at the 10 'dispenser.
  • the latter and the eluent containers can be placed in communication with a chromatography column 18 via a line C11 and an injection pump 17.
  • a detection device comprising several detectors 19a, 19b, 19c is disposed at the outlet of the column. Downstream of these detectors, the column 18 is connected to a pipe C20.
  • Collector containers 20 to 26 can be placed in communication with the line C20 by means of respective solenoid valves V20 to V26.
  • the container 20 is intended to collect the discarded part while the containers 21 to 26 are intended to collect the eluents containing the products to be recovered.
  • Each of the containers 10 to 16 is provided with a level probe, respectively S10 to S16, intended to provide a signal (SBO to SB6) when the level of liquid in the container becomes below a predetermined minimum threshold corresponding to the location of the probe in the container.
  • Similar probes S20 to S26 are placed in containers 20 to 26 but are intended to provide a signal (SHO to SH6) when the liquid level in the container becomes above a predetermined maximum threshold.
  • Two other probes SB10 'and SH10' are placed in the dosing container 10 at different heights, the difference in level between the low probe SB10 'and the high probe SH10' determining the volume of a dose of product to be fractionated.
  • a pressure sensor can be arranged between the pump 17 and the top of the column 18 to provide on an input of the door 01 a signal intended to control the stopping of the pump in the event of abnormal overpressure.
  • the unit 30 further comprises a control device 32 which receives the signals SD1 and SD2 produced by the probes SB10 'and SH10' as well as measurement signals SW, SCO and SpH supplied by the detectors 19a, 19b and 19c and representative of different characteristics of the liquid leaving the column. In response to the signals received, the device 32 controls the solenoid valves V'10, V10 to V16 and V20 to V26 by means of respective signals SV'10, SV10 to SV16 and SV20 to SV26.
  • the SUV, SCO and SpH signals are also transmitted to a multi-channel graphic recorder 39.
  • Eluents are solutions whose chemical composition can be identical or different with possibly different concentration and pH levels.
  • the admission of elected officials is most often carried out in increasing order of concentrations, the eluting power being higher in these cases the higher the concentration, whereas such a rule is not true for pH.
  • a measurement signal is supplied by a detector and representative of a characteristic of the liquid leaving the column and the corresponding fraction is collected during all or part of a peak in the measurement signal.
  • the first eluent is again admitted to the column for a rebalancing thereof for a new cycle.
  • the installation shown in Figure 1 allows the automatic realization of the operations indicated above.
  • six eluent containers 11 to 16 and six fraction collecting containers 21 to 26 are provided.
  • the number of eluent containers and fraction collecting containers can be chosen less than or more than six, as required.
  • the detectors 19a, 19b, 19c supply the control device with the information necessary for detecting the balance of the column and the peaks.
  • several detectors of different types are used.
  • One or more of these detectors can be assigned to detect the balance of the column while the detection of the peaks is made on the signal of at least one other detector.
  • any detector of known type can be used, depending in particular on the nature of the fractions to be collected, for example an ultra-violet detector 19a.
  • This detector comprises a tube 40 made of insulating material, for example glass, inserted by means of fittings 41, 42 on a pipe 43 connected in bypass on the outlet pipe of the column.
  • the central passage 44 of the tube 40 is traversed by the liquid whose ion concentration is to be measured.
  • This passage 44 is of relatively small diameter (for example 1 to 2 mm).
  • a coil 45 surrounds the tube 40, a variation in the concentration of the liquid in the tube causing a corresponding variation in the inductance of the coil. This is connected to a circuit 46 which produces the SCO signal representative of the lead of coil 45.
  • Circuit 46 comprises an oscillator 47 stabilized by a quartz 48 and providing a high frequency signal applied in a manner symmetrical with two branches 49a, 49b via a resistive divider 50.
  • the branch 49a comprises, in series two capacitors 51a, 52a, and a diode 53a between the divider 50 and an input of a differential amplifier 54.
  • a resonant circuit 55a formed by an adjustable capacitor 56a in parallel on a coil 57a is connected between the point common to the capacitors 51a, 52a and the ground.
  • the branch 49b is connected between the divider 50 and the other input of the amplifier 54 and has a structure identical to that of branch 49a, the coil of the resonant circuit being constituted by coil 45.
  • the imbalance between branches 49a and 49b reflects the value of the ion concentration in the liquid which passes through the tube 40 and is transformed into an SCO signal at the output of the amplifier 54.
  • the resonant circuits are tuned to a frequency slightly different from that of the signal supplied by the oscillator 47, the adjustment being such that the range of concentrations to be measured corresponds to a substantially linear part of the falling (or rising) portion of the resonance curve.
  • control device 32 will now be described in more detail with reference to FIGS. 3 to 9.
  • This control device essentially comprises a circuit 34 for balancing detection of the column 18, a circuit 35 for controlling the injection of a dose of product to be fractionated, a circuit 36 for controlling fraction collection and a switching circuit 37.
  • Circuit 34 (FIG. 4) comprises a circuit 34a which receives the measurement signal SpH and a reference signal spH supplied by an adjustment potentiometer PpH, and a circuit 34b which receives the measurement signal SCO and a reference signal sCO supplied by a PCO adjustment potentiometer.
  • the signal spH is applied by a resistor 70, on the one hand to the input of a Darlington circuit 71 to two transistors T1, T2 and, on the other hand, to a node P1, through a resistor 72.
  • the emitter-collector path of transistor T2 is in series with a resistor 73 between a terminal at potential + V and ground while the emitter of T2 is connected to a node P2 by a resistor 74.
  • An adjustable resistor 75 is connected between P1 and P2. Thanks to this arrangement, there exists between the nodes P1 and F2- a potential reference ⁇ pH of constant amplitude whatever the potential of point P1 or P2.
  • the potentiometer PpH makes it possible to adjust this potential and therefore to move within a given adjustment range a "window" of potential of given width ⁇ pH, this width being itself adjustable by action on the adjustable resistor 75.
  • the points P1 and P2 are connected by respective resistors 76, 77 to two points P3, P4 between which an adjustable resistor 78 is connected.
  • the resistors 76, 77 and 78 form a voltage divider which makes it possible to define between points P3 and P4 a second potential window ⁇ pH included in the first.
  • the width of this second window is less than that of the first and adjustable by the resistor 78.
  • the second window is located in the center of the first.
  • the points P 1 and P3 are connected respectively to the non-inverting inputs of two amplifiers 81, 83 while the points P2 and P4 are connected respectively to the inverting inputs of two amplifiers 82, 84.
  • the signal SpH is applied, via of a resistor 79, to the inverting inputs of amplifiers 81, 83 and to the non-inverting inputs of amplifiers 82, 84.
  • the outputs of amplifiers 81 and 82 are connected to the inputs of a gate 85 of ET type, and a light-emitting diode LED1 is connected in series with a resistor 87 between ground and the output of gate 85.
  • the outputs of amplifiers 83 and 84 are connected to the inputs of a gate 88 of ET type whose output is connected to ground by via a resistor 89 and another light-emitting diode LED2.
  • the presetting of circuit 34a is carried out by circulating directly in the pH detector 19c the eluent with which the column is subsequently to be balanced and by adjusting the potentiometer PpH until the diode LED2 lights up.
  • the pH reference value then corresponds approximately to the middle of the ⁇ pH window. Then, for the detection of the balance of the column, only signal A is used which indicates that the pH is between the limits pH1 and pH2, in the window ⁇ pH.
  • circuit 34b The structure and operation of circuit 34b are identical to that of circuit 34a.
  • a light-emitting diode LED'2 is used for the presetting of this circuit by means of the potentiometer PCO when the eluent flows directly into the concentration detector 19b. Then, during balancing of the column, a signal B is produced and a diode LED'1 lights up when the concentration is between limits C01 and C02 in the preset window ⁇ CO.
  • An ET gate 90 receives signals A and B and provides a signal C when the measured pH and concentration are within predetermined limits.
  • signal C is not directly taken into account but triggers a monostable circuit 91 which, in turn, triggers a second monostable circuit 92.
  • Circuit 91 generates a pulse of relatively long duration, for example one minute. Such a duration is long compared to the transient phenomenon represented by the passage of an air bubble but short compared to the duration of the phases of a chromatography cycle.
  • Circuit 92 generates a pulse of much shorter duration.
  • the outputs of door 90 and monostable 92 are connected to the inputs of a door 93 of type ET.
  • the output signal from gate 93 is applied to an input of a gate 94 of ET type and to an input X of a flip-flop 95.
  • an output terminal of the flip-flop 95 goes to low logic level, which blocks gate 94.
  • monostable 91 is triggered and if signal C is still present at the end of the pulse delivered by this monostable, signal D is emitted and a balance detection pulse DE is produced at the output of gate 94.
  • Signal D also triggers flip-flop 95 which prevents any subsequent signal D from being taken into account until the flip-flop 95 is reset by an RS signal. applied to an input Y of flip-flop 95.
  • Each of the probes SB10 ', SH10' includes a pair of contacts spaced from each other. One of the contacts is grounded while the other is connected to a potential + V , by a high impedance resistance, and to an inverting gate, respectively 101, 102.
  • the signals SD1, SD2 of the probes SB10 ' , SH10 ' are inverted by the inverting doors 101, 102 whose output goes to high logic level when the probes are wet.
  • the output signals of the doors 101, 102 are applied, on the one hand, respectively to two reversing doors 103, 104 and, on the other hand to the two inputs of a door 105 of type ET.
  • valve V11 With valve V11 still open, a new cycle begins again when the column is again balanced with the eluent.
  • the installation described above has the considerable advantage to limit operator interventions, for a given chromatography to variable g spinning thresholds and monitoring the levels in the containers.

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  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Biochemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Fluid Mechanics (AREA)
  • Treatment Of Liquids With Adsorbents In General (AREA)
EP83401880A 1982-09-28 1983-09-27 Automatische Anlage für Flüssigkeitschromatograpie Expired EP0107544B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR8216302A FR2533456A1 (fr) 1982-09-28 1982-09-28 Installation automatique pour chromatographie liquide
FR8216302 1982-09-28

Publications (3)

Publication Number Publication Date
EP0107544A2 true EP0107544A2 (de) 1984-05-02
EP0107544A3 EP0107544A3 (en) 1984-06-20
EP0107544B1 EP0107544B1 (de) 1986-12-30

Family

ID=9277809

Family Applications (1)

Application Number Title Priority Date Filing Date
EP83401880A Expired EP0107544B1 (de) 1982-09-28 1983-09-27 Automatische Anlage für Flüssigkeitschromatograpie

Country Status (8)

Country Link
EP (1) EP0107544B1 (de)
JP (1) JPS5983053A (de)
CA (1) CA1217728A (de)
DE (1) DE3368530D1 (de)
DK (1) DK161498C (de)
FR (1) FR2533456A1 (de)
IE (1) IE54651B1 (de)
NO (1) NO159433C (de)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2705582A1 (fr) * 1993-05-25 1994-12-02 Commissariat Energie Atomique Dispositif automatique de traitement par chromatographie sur colonne et détecteur de liquide utilisable dans un tel dispositif.
WO1996012543A1 (en) * 1994-10-24 1996-05-02 Aranda Scientific Instruments Pty. Ltd. Methods and apparatus for protection of liquid chromatography columns

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61215962A (ja) * 1985-03-22 1986-09-25 Yamazen Kk フラクシヨンコレクタ−
JPS6396552A (ja) * 1986-10-14 1988-04-27 Suntory Ltd 生体高分子の工業的分離法、その方法に使用する装置

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2692820A (en) * 1950-10-28 1954-10-26 Upjohn Co Method and means for effecting automatic fractionation
US3701609A (en) * 1971-05-13 1972-10-31 David G Bailey Apparatus for automatically adding preselected patterns of eluent solutions to a chromatographic column and monitoring and collecting eluted fractions
US3826905A (en) * 1971-10-27 1974-07-30 Suomen Sokeri Oy Methods and apparatus for providing automatic control of chromatographic fractionating processes
JPS5123360A (ja) * 1974-08-15 1976-02-24 Teijin Ltd Yokoitotanchisochi
FR2388585A1 (fr) * 1977-04-26 1978-11-24 Elf Aquitaine Separation et purification de proteines et/ou d'unites morphologiquement organisees (virus) par la chromatographie d'exclusion
US4116046A (en) * 1977-08-05 1978-09-26 Hoffmann-La Roche Inc. Liquid chromatography system
DE3030069A1 (de) * 1980-08-08 1982-03-11 Philips Patentverwaltung Gmbh, 2000 Hamburg Anordnung zur messung des elektrischen flaechenwiderstandes elektrisch leitender schichten

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2705582A1 (fr) * 1993-05-25 1994-12-02 Commissariat Energie Atomique Dispositif automatique de traitement par chromatographie sur colonne et détecteur de liquide utilisable dans un tel dispositif.
WO1996012543A1 (en) * 1994-10-24 1996-05-02 Aranda Scientific Instruments Pty. Ltd. Methods and apparatus for protection of liquid chromatography columns

Also Published As

Publication number Publication date
DK444983A (da) 1984-03-29
NO833481L (no) 1984-03-29
DK161498C (da) 1991-12-23
DK161498B (da) 1991-07-15
IE54651B1 (en) 1989-12-20
FR2533456A1 (fr) 1984-03-30
JPS5983053A (ja) 1984-05-14
NO159433C (no) 1988-12-28
EP0107544A3 (en) 1984-06-20
CA1217728A (en) 1987-02-10
EP0107544B1 (de) 1986-12-30
DE3368530D1 (en) 1987-02-05
IE832227L (en) 1984-03-28
FR2533456B1 (de) 1985-03-29
DK444983D0 (da) 1983-09-28
NO159433B (no) 1988-09-19

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